title: Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells.
abstract: The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34(+)) leukemic versus normal specimens. Our data indicate that CD34(+) AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34(+) AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34(+) cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34(+) AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34(+) cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells.
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, New York 14642; Department of Medicine, University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Pei
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Minhajuddin
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Callahan
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Marlene
authors.initials: M
authors.lastname: Balys
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: John M
authors.initials: JM
authors.lastname: Ashton
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Neering
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Eleni D
authors.initials: ED
authors.lastname: Lagadinou
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Corbett
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado 80045; Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Haobin
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Liesveld
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: O'Dwyer
authors.affiliation: Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York 10021; Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York 10021.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129.
authors.forename: Cyril
authors.initials: C
authors.lastname: Benes
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Fred K
authors.initials: FK
authors.lastname: Hagen
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Joshua
authors.initials: J
authors.lastname: Munger
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas, Little Rock, Arkansas 72205.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.affiliation: Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Becker
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, New York 14642; Department of Medicine, University of Colorado Denver, Aurora, Colorado 80045. Electronic address: craig.jordan@ucdenver.edu.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018952:Antigens, CD34; D004148:Dioxolanes / Q000494:pharmacology*; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D012717:Sesquiterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000094765:Glutathione Peroxidase GPX1; D010881:Piperidones
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018952:Antigens, CD34; D004148:Dioxolanes; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D005979:Glutathione Peroxidase; D012717:Sesquiterpenes; D000094765:Glutathione Peroxidase GPX1; C002669:parthenolide; C546365:GCLM protein, human; C498077:piperlongumine; D010881:Piperidones; C000722067:GPX1 protein, human
keywords: Anticancer Drug; CD34+; Cancer Stem Cells; Glutathione; Human; Leukemia; Parthenolide; Redox Regulation; Tumor Metabolism